Role of Sirtuin 1 in the Regulation of Hepatic Gene Expression by Thyroid Hormone

Sirtuin 1 (SIRT1) is a nuclear deacetylase that modulates lipid metabolism and enhances mitochondrial activity. SIRT1 targets multiple transcription factors and coactivators. Thyroid hormone (T-3) stimulates the expression of hepatic genes involved in mitochondrial fatty acid oxidation and gluconeogenesis. We reported that T-3 induces genes for carnitine palmitoyltransferase (cpt1a), pyruvate dehydrogenase kinase 4 (pdk4), and phosphoenolpyruvate carboxykinase (pepck). SIRT1 increases the expression of these genes via the activation of several factors, including peroxisome proliferator-activated receptor alpha, estrogen-related receptor alpha, and peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha). Previously, we reported that PGC-1 alpha participates in the T-3 induction of cpt1a and pdk4 in the liver. Given the overlapping targets of T-3 and SIRT1, we investigated whether SIRT1 participated in the T-3 regulation of these genes. Resveratrol is a small phenolic compound whose actions include the activation of SIRT1. Addition of resveratrol increased the T-3 induction of the pdk4 and cpt1a genes in hepatocytes. Furthermore, expression of SIRT1 in hepatocytes mimicked resveratrol in the regulation of gene expression by T-3. The deacetylase activity of SIRT1 was required and PGC-1 alpha was deacetylated following addition of T-3. We found that SIRT1 interacted directly with T-3 receptor (TR beta). Knockdown of SIRT1 decreased the T-3 induction of cpt1a and pdk4 and reduced the T-3 inhibition of sterol response element binding protein (srebp-1c) both in isolated hepatocytes and in rat liver. Our results indicate that SIRT1 contributes to the T-3 regulation of hepatic genes.